While 80% of melanomas harbor mutation in genes that activate the MEK-MAPK signaling pathway, over 50% of melanomas also exhibit upregulation of the AKT/PI3K signaling cascade. Given that inhibitors to components of the MEK/MAPK signaling cascade are not sufficient enough to halt melanoma progression, it is now recognized that combination therapy in melanoma is inevitable. More and more studies provide sound support for the notion that PI3K/Akt is likely to serve as the excellent candidate for combined therapy. Among mechanisms underlying PI3K/Akt contribution to melanoma development is its effect on hypoxia and tumor microenvironment, although underlying mechanisms are not well understood. Among Pten/Akt effectors that play important role in the regulation of HIFIa availability is the ubiquitin ligase Siah2, which is transcriptionally upregulated by Akt. Correspondingly, increased expression of Siah2 is found in malignant melanoma. Further, inhibition of Siah2 effectively blocks melanoma growth and progression. These finding provide the rationale to develop inhibitors to Akt and Siah2 as select targets for treatment of this tumor type. Thus, we propose to use a combination of chemical library screening, structure-based design and medicinal chemistry approaches to obtain potent and selective inhibitors of Akt and Siah. In close collaboration with Project 1 and Core B and C the compounds will be tested in vitro, in 3D cell cultures and in in vivo efficacy and toxicity studies. Overall, our main objective is to develop novel safe and effective agents that by targeting specific genes such as Akt and Siah, which would provide compelling alternative strategies for the treatment of melanoma.